We have been studying the molecular control of circadian behavioral rhythms using Drosophila as a model system. Homologues of genes initially characterized in the fly, have now been linked to the control of rhythmic behavior and physiology in vertebrates, including fish, frogs, mice and humans. We propose investigations of two kinases, GSK-3 and DBT, in the clocks of Drosophila and mammals. Some of our preliminary work suggests a novel approach to the study of certain human depressive disorders. Other aspects of our work could identify new output pathways from the clock that organize circadian behavioral and physiological responses. The following will be addressed: (1) Does GSK3 have a central role in the mammalian clockworks as it does in Drosophila? How do lithium and valproic acid, preferred agents for managing bipolar disorder, stop the circadian clock? (2) Does GSK-3 affect the fly clock by phosphorylating TIM? Is GSK-3 activity required for PER/TIM nuclear translocation? (3) Does TIM have a role in the mammalian clock? (4) What are the in vitro activities of DBT? (5) Does DBT-dependent phosphorylation regulate nuclear accumulation of PER? How does PER phosphorylation influence phosphorylation of TIM? (6) Does DBT's physical association with PER put other substrates of the kinase under circadian control? [unreadable] [unreadable]